Acute lymphoblastic leukemia

What every physician needs to know:

Acute lymphoblastic leukemia (ALL) is a neoplasm involving precursor lymphoblasts committed to either the B-cell or T-cell lineage. ALL is primarily a disease of children, with about 75% of cases occurring in patients under 6 years of age. The incidence of ALL is about 2 per 100,000 persons per year, with 6,000 new cases diagnosed each year in the United States of America. Approximately 85% are precursor B-cell phenotype, with precursor T-cell disease accounting for the remainder.

There has been tremendous progress in the treatment of childhood ALL over the past several decades. Current trials for pediatric ALL have reported complete remission (CR) rates of 95% to 99%, with estimated 5 year event free survival (EFS) rates of 80% to 85%. Children are risk stratified based on their age, white blood cell count, and immunophenotype. For standard risk patients, the 5 year EFS approaches 85%, with a 5 year disease free survival (DFS) of 85% to 90%. For high-risk patients, the outcome is slightly inferior to that of standard-risk patients with a 5 year EFS of 75% and a 5 year DFS of 78%. Because standard risk patients have done remarkably well, efforts are now focusing on reducing therapy, including decreases in both systemic and central nervous system (CNS) treatment.

Unfortunately, the results for adults with ALL have not kept pace with those of children, with a DFS of only 41%, and an overall survival (OS) rate of 43%.

Are you sure your patient has acute lymphoblastic leukemia? What should you expect to find?

Presentation

The clinical presentation of patients with ALL is often insidious.

Symptoms include fatigue, lethargy, or the presence of constitutional symptoms such as fevers, night sweats, or weight loss. In addition, patients can present with symptoms resulting from anemia, such as dyspnea or lightheadedness, infections due to neutropenia, or easy bruisability or bleeding resulting from thrombocytopenia.

Children often have a more aggressive and dramatic presentation that may result in extreme pain in the extremities and joints and can be confused with arthritis. Lymphadenopathy, splenomegaly, and hepatomegaly is seen in about 20% of patients with ALL.

Abdominal masses are uncommon and if present suggest mature B-cell ALL (Burkitt's lymphoma/leukemia). Symptoms from CNS involvement at presentation is rare, and if present often manifest as symptoms from cranial nerve involvement, due to leptomeningeal leukemic deposits.

Acute lymphoblastic leukemia/lymphoma definition

Acute lymphoblastic leukemia is typically associated with a proliferation of small to medium sized blasts with scant agranular cytoplasm involving primarily the bone marrow and the peripheral blood. Patients may also present with primary involvement of nodal or extranodal sites, which occurs much more commonly in patients with T-cell ALL.

The term ALL is used when the lymphoblasts involve primarily the bone marrow and the peripheral blood, while the term lymphoblastic lymphoma (LBL) is used when the disease involves primarily a node or an extranodal mass. In patients who have both bone marrow involvement and a mass lesion, the distinction between ALL and LBL is arbitrary. There is no agreed upon number of lymphoblasts that is required for a diagnosis of ALL, and patients may rarely present with low blast counts. It is important to note that the term B-ALL should NOT be used to refer to cases that are diagnosed as Burkitt's leukemia/lymphoma.

Similar to cases of B-ALL, the bone marrow is involved in all cases of T-ALL (T-cell ALL), but an "aleukemic" presentation with very few circulating lymphoblasts is uncommon. Patients with T-LBL (T-cell lymphoblastic leukemia)typically present with a large mediastinal (thymic) mass, and may also have nodal or extranodal involvement at other sites. T-LBL can involve any lymph node or extranodal site; skin, tonsil, liver, spleen, CNS, and testis (in males) are the most common. In contrast, patients with B-LBL (B-cell lymphoblastic leukemia)commonly have involvement of skin, soft tissue, bone, or lymph nodes, but mediastinal involvement is exceedingly rare.

Laboratory evaluation defines a large number of specific genetic subsets of ALL, as outlined below.

Beware of other conditions that can mimic acute lymphoblastic leukemia:

The differential diagnosis for patients with ALL is broad. For patients with pancytopenia and an aleukemic presentation, that is, no circulating lymphoblasts, the differential includes acute myeloid leukemia and marrow failure syndromes such as myelodysplastic syndrome or aplastic anemia.

Children and young adults who present with severe back, joint or extremity pain, are often referred to a rheumatologist for evaluation of Still's disease and other rheumatologic disorders.

In patients who present with circulating blasts, ALL must be distinguished from other leukemic disorders such as mature B-cell leukemia (Burkitt's leukemia), acute myelogenous leukemia, chronic lymphocytic leukemia, prolymphocytic leukemia, and the leukemic phase of several lymphomas, such as blastic phase mantle cell lymphoma.

The differential between Philadelphia chromosome-positive ALL and chronic myeloid leukemia (CML) in lymphoid blast crisis is purely academic, since the treatment for both are similar. The p210 BCR-ABLtranscript is seen in 99% of cases of CML, whereas the p190 transcript is seen in 90% of cases of pediatric Philadelphia positive ALL and in about 50% of adult cases.

Which individuals are most at risk for developing acute lymphoblastic leukemia:

ALL/LBL is a rare event and, at least in children, there is no known heritable factor leading to disease.

In adults, ALL may arise after exposure to chemotherapy, specifically topoisomerase I and II inhibitors such as etoposide, which is used to treat testicular and other germ cell tumors, and anthracyclines such as doxorubicin, which is used to treat a wide variety of cancers such as breast, ovarian, lung, sarcomas of bone and soft tissue, as well as lymphomas. The cases of therapy related ALL or secondary ALL (as they are sometimes termed) often involve the MLL gene on chromosome 11q23.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

ALL is diagnosed by the detection of lymphoblasts in the peripheral blood or bone marrow. Lymphoblasts are characterized by their morphologic, cytochemical, and immunophenotypic characteristics as described below.

Morphology

Lymphoblasts in B-ALL (B-cell ALL)/LBL and T-ALL/LBL are indistinguishable, are typically small to intermediate sized, and have scant cytoplasm, with a high nuclear to cytoplasmic ratio. The nucleolus is often indistinct, and the cytoplasm varies from blue to blue-grey in color with occasional vacuoles. The lymphoblasts can have a cytoplasmic pseudopod, and such cells are often referred to as "hand mirror" cells. Lymphoblasts can be distinguished from their normal B-cell precursors by the fact that the latter have a higher nuclear to cytoplasmic ratio, homogeneous chromatin, and no obvious nucleoli.

Cytochemistry

Cytochemistry is formerly used to distinguish ALL from myeloid leukemia, although it is much less helpful in the era of immunophenotyping. Both B- and T-cell lymphoblasts are negative for myeloperoxidase. B-cell, but not T-cell, lymphoblasts are often positive for PAS (periodic acid-Schiff) stain in a coarse "block-like" pattern. Positive PAS stain is a marker of intracellular glycogen, which is often present in B-cells.

Immunophenotype

The most important method used to diagnose ALL/LBL is immunophenotyping by flow cytometry of either the peripheral blood or the bone marrow. B-ALL/LBL lymphoblasts are almost always positive for CD19, cytoplasmic CD22, and CD79a. In addition, most cases also express CD10, surface CD22, CD24, paired box protein Pax-5 (PAX5), and terminal deoxynucleotidyl transferase (TdT). Expression of both CD20 and CD34 is variable and staining for CD45 is dim.

Some cases of B-ALL/LBL express the myeloid antigens CD13 and CD33, which often reflects the presence of the Philadelphia chromosome, t(9;22), or MLL rearrangement on chromosome 11q23. Surface immunoglobulin rearrangement occurs after the precursor B-cell stage, and therefore its expression on the cell surface is usually absent. However, the presence of faint immunoglobulin staining does not by itself exclude the diagnosis of B-ALL/LBL, if the immunophenotypic, morphologic, and cytogenetic data otherwise support the diagnosis.

Cytogenetics

Cytogenetic analysis should be performed on the bone marrow or peripheral blood of all patients with ALL.

Cytogenetic and immunophenotypic analysis serves to define several genetic subsets of the disease as shown below.

B-ALL/LBL

Philadelphia chromosome positive (Ph+) ALL

BCR-ABL1associated ALL arises from a reciprocal translocation involving chromosomes 9 and 22, t(9;22)(q34;q11.2). The frequency of Ph+ ALL increases with age. It is found in less than 3% of children, but is found in about 25 to 30% of adult patients. The Ph+ stem cell is thought to be more primitive than other B-ALL initiating cells, and as a result, Ph+ ALL has a poor prognosis. Patients with Ph+ ALL are treated with combination chemotherapy, including a tyrosine kinase inhibitor (TKI) such as imatinib or dasatinib. Remission rates now approach 100%, with a 3 year disease free survival (DFS) of about 50%. The standard approach is to consolidate all patients with Ph+ ALL, with an allogeneic stem cell transplant (AlloSCT) in first remission.

Mixed lineage leukemia (MLL)

The MLL gene is at 11q23 and chromosomal translocation involving the MLL locus is associated with a large variety of fusion proteins. The most common includes the AF4 gene, t(4;11). MLL rearrangements may occur in utero, as approximately half of all infant ALL (less than 12 months of age) have MLL translocations. Lymphoblasts with MLL rearrangements are morphologically and cytochemically identical to other subtypes of B-ALL, but immunophenotypically, they are often CD10 (common acute lymphoblastic antigen, CALLA) negative. Patients with MLL-AF9 translocations tend to have a poor prognosis and most patients will undergo AlloSCT in first remission. The prognosis of other MLL translocations is unclear.

TEL-AML1 (ETV-RUNX1) ALL

The TEL-AML1 translocation, t(12;21)(p13;q22) is the most common chromosomal translocation in the pediatric population, accounting for about one quarter of all cases. Interestingly, it is seldom seen in patients over the age of 21 years. The ETV6-RUNX1 translocation is likely an early event in leukemogenesis, as it can be identified in neonatal blood spots in children who develop B-ALL years later. The presence of the TEL-AML1 translocation confers a favorable prognosis, as more than 90% of patients are cured with chemotherapy.

Hyperdiploid ALL

B-ALL blasts that contain more than 50 chromosomes are seen in about 25% of pediatric patients and less frequently in older patients. The extra chromosomes are not random, with trisomy of chromosomes 21, X, 14, and 4 being most common. It is the specific combination of chromosomes that predicts prognosis and not the overall number. Trisomies of 4, 10, and 17 carry the best overall prognosis.

Hypodiploid ALL

Patients with B-ALL and blasts that contain less than 45 chromosomes, and particularly those with less than 44, have an unusually poor prognosis. This phenotype is seen in about 5% of both children and adults.

E2A-PBX1 (TCF3-PBX1) ALL

The translocation t(1;19)(q23;p13.3) generates a fusion of theE2A (TCF3) gene on chromosome 19 and the PBX1 gene on chromosome 1. The lymphoblasts are usually positive for both CD19 and CD10. Historically, patients with E2A-PBX1 positive B-ALL had a poor prognosis, but the outcomes have greatly improved with more intensive chemotherapy strategies.

Ikaros and CRLF2 mutations

Both Ikaros and CRLF2 are expressed in about 15% of all cases of B-ALL, regardless of other genetic abnormalities. Expression of these proteins confers an extremely poor prognosis, and the most appropriate treatment strategy for these patients remains undefined.

T-ALL/LBL

Abnormal karyotypes are found in about 50% of cases of T-ALL/LBL. The most common abnormality involves the delta T-cell receptor (TCR) at 14q11, the beta TCR at 7q35 or the gamma TCR at 7p14. These translocations lead to disruption of the TCR partner gene, the most common being the HOX11 and HOX11L2 genes. Approximately 50% of cases of adult and pediatric T-ALL/LBL contain activating mutations of the NOTCH1 gene, either within the extracellular heterodimerization domain or within the C-terminal PEST (proline-glutamate-serine-threonine-rich) domain. In addition, 30% of patients have mutations in the FBXW7 gene, which is a negative regulator of NOTCH1.

T-ALL/LBL can be separated into four distinct subtypes based on immunophenotype patterns that correspond to different stages of intrathymic differentiation; the best prognosis is seen in patients with the thymic (cortical) phenotype.

Pro-T ALL/LBL

Positive for cytoplasmic CD3 and CD7, and negative for CD1a, CD2, CD4 and CD8.

Pre-T ALL/LBL

Positive for cytoplasmic CD3, CD2, and CD7, but negative for CD1a, CD4 and CD8.

Cortical (thymic) T ALL/LBL

Positive for cytoplasmic CD3, CD1a, CD2 and CD7, as well as usually positive for both CD4 and CD8.

Mature (medullary) T ALL/LBL

Positive for cytoplasmic and surface CD3, CD2 and CD7, but negative for CD1a. They are usually only positive for either CD4 or CD8.

What imaging studies (if any) will be helpful in making or excluding the diagnosis of acute lymphoblastic leukemia?

N/A

If you decide the patient has acute lymphoblastic leukemia, what therapies should you initiate immediately?

Once a diagnosis of ALL is made, it is imperative to initiate definitive therapy immediately.

Steroids are a significant anti-leukemic therapy and should not be started until a definitive diagnosis is made and staging procedures completed. This includes lumbar puncture, if indicated. Once a diagnosis is confirmed, many regimens employ a steroid prophase that should be considered as part of definitive therapy.

More definitive therapies?

Age and treatment

Age is a continuous variable, and age restrictions on clinical trial participation are arbitrary. Recent data suggest that the outcome of older adolescents (aged 16 to 21 years) with ALL is improved if they are treated on intensive pediatric protocols, rather than on less intense adult protocols. A retrospective study from France compared patients aged 15 to 20 years that were treated either on the pediatric French Acute Lymphoblastic Leukemia Group (FRALLE)-93 protocol or on the adult Leucémie Aigüe Lymphoblastique de l'Adulte-94 (LALA-94) protocol. The CR rate for the 77 patients on the pediatric trial was 94%, compared to 83% for the 100 patients treated on the Leucémie Aigüe Lymphoblastique de l'Adulte (LALA-94) trial.

With a median follow-up of 3.5 years, the estimated 5 year EFS and DFS rates for the patients who achieved a CR were superior for those treated on the pediatric as opposed to the adult clinical trials (67% versus 41% and 72% versus 49%). The cohorts were well-matched for sex, immunophenotype, and cytogenetic profiling, and the multivariate analysis revealed an independent influence of the treatment regimen on prognosis. Differences in drug and dose intensity may explain the superior results with the pediatric FRALLE-93 regimen, as the pediatric trial used five times more prednisone than the adult study. Also, 50% more prednisone was used during the induction course, and three times more vinca alkaloids and 20 more doses of L-asparaginase were administered to patients in the FRALLE study as compared to the LALA-94 trial.

The Cancer and Leukemia Group B (CALGB) and the Children's Cancer Group (CCG) have presented a similar analysis by comparing patients aged 16 to 21 years who were treated between 1988 and 1998 on sequential trials. A large retrospective cohort analysis compared 103 patients treated on CALGB studies, to 196 patients treated by various CCG centers. The groups were surprisingly well controlled for age, sex, immunophenotype, white blood cell (WBC) count, and cytogenetic abnormalities. Although the CR rates were similar between the groups treated by the CCG (96%) and CALGB (93%), the 6 year EFS rates were highly discordant, being 64% among those treated on CCG trials and only 38% among similar patients treated by the CALGB.

Why adolescent adults fare more favorably when treated on pediatric ALL protocols is unclear. Dose intensity is clearly greater within the pediatric protocols, especially with such agents as asparaginase, vincristine, corticosteroids, and methotrexate. For example, the dose of vincristine was capped at 2mg in adult trials. However, the CALGB regimen was inferior to the CCG protocol, despite the administration of 14 doses of asparaginase over a 7 week period within the first 3 months. Differences in therapeutic practices may be equally important. Frequently, longer delays are encountered during therapy on adult trials, compared with pediatric protocols. In addition, pediatric hematologists typically administer chemotherapy agents with greater adherence to schedules and dose density.

The CALGB initiated a five-drug induction regimen starting with protocol 8811. This trial added cyclophosphamide and asparaginase during induction and early intensification. The consolidation and maintenance regimens were similar to the German Berlin-Frankfurt-Munster (BFM) multicenter trials. A subsequent study (CALGB9111) randomized patients to the addition of filgrastim (granulocyte colony-stimulating factor, G-CSF), which resulted in a statistically significant improvement in CR rate to 87% compared with 77% in the placebo arm. However, no improvements were seen in the 3 year DFS rate of 41% or the OS rate of 43%.

Current CALGB trials are using a modular A-B-C regimen (protocols 19802 and 10102), characterized by dose intensive daunorubicin followed by high-dose methotrexate and cytarabine consolidation therapy. CR rates remain about 78%, with a median OS of about 19 months. Other adult ALL regiments include the hyper-CVAD regimen, which consists of alternating cycles of cyclophosphamide, vincristine, doxorubicin, and dexamethasone with cycles of methotrexate and cytarabine. CR rates using hyper-CVAD approach 90% with a 5 year DFS and OS rate of 38%. Similar results have been reported by the Medical Research Council (MRC) and the German multicenter trials.

The treatment of Philadelphia chromosome positive ALL depends on the patient’s age. For younger adult patients, multi-agent chemotherapy with the addition of a tyrosine kinase inhibitor (TKI) is typically used. The choice of TKI includes imatinib (Gleevec) or dasatinib (Sprycel). There are numerous chemotherapy backbone regimens that are commonly used. These include hyper-CVAD and the five drug CALGB or Larson regimen. Hyper-CVAD can be combined with either imatinib or dasatinib, which results in improved complete remission rates, disease free survival, and overall survival rates as compared to chemotherapy without the addition of a TKI.

Most patients in remission proceed towards an allogeneic stem cell transplant with retrospective data, suggesting that patients benefit from stem cell transplantation in first remission. Other common chemotherapy regimens currently in use, include the five drug induction regiment from the CALGB (see Larson 1998 reference below), as well the Eastern Cooperative Oncology Group (ECOG)2993 regimen. There seems to be no significant difference in the complete remission in overall survival rates between these regiments, however, none have been compared in a randomized phase III trial.

For patients who are older, the Italian group GIMEMA has published a series of studies combining TKIs with steroids. The first published by Vignetti et al, demonstrated that imatinib plus corticosteroids was extremely well tolerated with a high remission rate; however, most patients relapsed within 1 year. A follow up study by Foa et al, combined dasatinib with steroids,and remission rate improved with extremely low treatment related mortality. Again half the patients relapsed within 1 year.

This is a reasonable option for older patients or for patients with significant co-morbidities. The role of non-myeloablative or reduced intensity stem cell transplantation in the elderly is untested in randomized studies. However, given the data in younger patients, this is a preferred approach for older patients without significant co-morbidities who enter remission and are eligible for transplantation.

Single agent therapy with TKIs have low complete remission rates, and remissions, if obtained, are not durable. Each of the approved TKIs, imatinib and dasatinib, have significant efficacy in patients with Philadelphia chromosome positive acute lymphoblastic leukemia. A newer agent now in clinical trials, ponatinib, is a pan-ABL inhibitor, and recent clinical trial demonstrated single agent activity even in refractory patients.

It is important to remember that patients with Philadelphia chromosome positive ALL still require CNS prophylaxis. Even in adult patients, where the goals of therapy may be palliative, CNS prophylaxis should be considered to avoid CNS relapse. Prophylaxis should be completed prior to stem cell transplantation.

A recent randomized study from the Eastern Cooperative Oncology Group (ECOG), ECOG2993/UKALL12 performed a large randomized trial. In this study, patients with Philadelphia negative disease who were under 55 years old, were assigned a sibling allogeneic transplant if they had a sibling donor, or if they did not have a sibling donor, then they were randomized to receive an autologous transplant or consolidation chemotherapy. In this study, analyzed on an intent-to-treat basis, there was an improved overall 5 year survival of 53% versus 45%, and a lower relapse rate survival for those patients who had a donor. The autologous transplant arm had a lower 5 year overall survival than those patient assigned to maintenance chemotherapy (37% versus 46%).

The difficulty in interpreting this study is that the only patients who benefited from transplant were those determined to be at "standard risk", based on white blood count, age, and cytogenetics. Patients with "high-risk" disease did not benefit from allogeneic transplant. High-risk disease was previously considered an indication for stem cell transplantation in first remission. In addition, young adult patients seem to benefit when treated on pediatric like or pediatric inspired regimens. It is difficult to determine the results of this study in this context. That is, would the same result have occurred if the control arm was a pediatric regimen?

It still remains reasonable to offer an allogeneic transplant to patients who are at high risk for relapse, specifically for patients with Philadelphia chromosome positive cytogenetic abnormality, a translocation involving chromosome 11q23, commonly the t(4;11) translocation, or patients with a hypodiploid karyotype (less than 45 chromosomes). The use of molecular risk analysis for patients with ALL is still in its infancy, but patients with Ikaros or CRLF2 mutations have a high risk for relapse and may also benefit from stem cell transplantation.

Long term complications of therapy for acute lymphoblastic leukemia

The therapy for patients with ALL is long and complicated. As a result, there are many potential complications. Long durations of corticosteroid use leads to immune suppression and an increased risk of infection. Infections often include fungal infections specifically Aspergillus. Corticosteroids also cause significant mood alterations, risk of hyperglycemia, and bone morbidity. In pediatric patients, this leads to growth plate fractures, and potential growth stunting as a result. In older adolescents and young adult patients, the use of high-dose corticosteroids is associated with avascular necrosis.

In addition, multi agent chemotherapy for ALL may result in hepatotoxicity due to the use of anthracyclines, vinca alkaloids, asparaginase or antimetabolites. The risk of hepatotoxicity is complicated by the use of other hepatically cleared agents, such as antibiotics and antifungal therapies.

What other therapies are helpful for reducing complications?

Central nervous system disease in acute lymphoblastic leukemia

In general, without prophylaxis, the CNS relapse rate approaches 25%, but can be reduced to less than 5 to 10% in patients with good systemic control and CNS directed therapy. CNS therapy includes either utilization of high dose methotrexate and frequent doses of intrathecal chemotherapy, with methotrexate or cytarabine. In many regimens, specifically with those patients with T-cell ALL, the use of cranial radiation is still employed. A recent Cancer and Leukemia Group B (CALGB) study administered high dose methotrexate and cytarabine without intrathecal therapy, using systemic therapy for CNS prophylaxis. This study demonstrated similar CNS relapse rates, but the added systemic therapy increased toxicity when compared to intrathecal therapy.

The rate of CNS relapse depends upon the ability to control systemic disease. Approximately 3 to 5% of pediatric patients will present with asymptomatic CNS involvement. It is less clear in adult patients, as the first CNS assessment is typically performed after the achievement of remission. Historically, children who present with CNS involvement, even when asymptomatic, had a poor overall diagnosis. The prognosis of these patients can be greatly improved with higher intensity CNS directed therapy.

Patients with CNS relapse typically present with leptomeningeal disease, and not intraparenchymal masses. Therefore, intrathecal therapy and radiation can be therapeutic in these instances. The use of cranial plus spinal radiation has to be used with extreme caution, as this may mitigate the ability to administer subsequent doses of systemic chemotherapy due to poor marrow reserves, specifically in older adult patients.

What should you tell the patient and the family about prognosis?

The prognosis of ALL is highly variable, and dependent on factors such as age, immunophenotype, and the presence of the Philadelphia chromosome or other cytogenetic or molecular abnormalities. This is outlined in "More definitive therapies".

What if scenarios.

Pancreatitis

Pancreatitis is a specific toxicity of asparaginase. It is more common in adolescents and young adult patients, as compared with young children. The risk of pancreatitis in young children is 8%, whereas in adolescents and young adult patients, the incidence increases to about 13%. In some cases, pancreatitis can be severe or even life threatening. However, patients often recover with fluid resuscitation, avoidance of parental feeding, and conservative management. The subsequent administration of asparaginase is typically avoided in patients who develop moderate to severe pancreatitis.

Treatment of relapsed acute lymphoblastic leukemia

The treatment of relapsed ALL is unfortunately a common occurrence, especially in adult patients. For patients who are Philadelphia chromosome negative, the timing of relapse is important.Late relapse is defined as greater than 12 months in complete remission, and this group of patients are often treated with reinduction chemotherapy using the identical initial regimen.For patients who suffer an early relapse, this approach is ineffective. Instead alternative chemotherapy regimens are used including regimens with high-dose cytarabine or clofarabine. Once in a second complete remission, patients proceed to an allogeneic transplant, but long tern disease free survival remains limited. In older patients or patients with significant co-morbidities, a palliative approach is usually offered.

Relapse in patients with Philadelphia chromosome positive ALL requires assessment of tyrosine kinase domain (TKD) mutations. Occasionally, the mutation analysis will suggest that an effective result can be obtained by changing to an alternative TKI. For patients who develop a T315I BCR-ABL mutation, there are no approved TKIs, but ponatinib, which is a novel pan-ABL inhibitor is currently in clinical trials and has shown activity against all BCR-ABL mutations including the T315I. Systemic chemotherapy remains an option for patients who have failed TKI based therapy, but long term control of the disease is often limited and palliative approaches should then be considered.

Testicular relapse

Testicular relapse is an uncommon occurrence with current strategies. The use of high dose methotrexate, common in pediatric studies, has significantly reduced the rate of testicular relapse, which is much more common in T-cell ALL/LBL. Therefore, a careful testicular exam is warranted at baseline in male patients with T-cell ALL or LBL, and should be part of a routine follow up examination. In order to confirm the diagnosis, an orchiectomy is required in order to differentiate between a germ cell tumor versus ALL/LBL. Treatment includes radiation therapy, CNS directed therapy, as well as systemic therapy. Pediatric patients with a late isolated testicular relapse can be cured with this approach without stem cell transplant. There is insufficient data in adult patients and most are taken to an allogeneic stem cell transplant, once they achieve a second remission.

Thrombosis

Thrombosis is relatively common in patients receiving asparaginase containing regimens. Asparaginase depletes patients of anti-thrombin 3 (AT3), causing a hypercoagulable state. Prophylaxis with low-molecular-weight heparin (LMWH) or replacement with AT3 may mitigate the risk; however, there is only limited prospective data. One should make every effort to avoid the use of fresh frozen plasma (FFP), since there is asparaginase in FFP and therefore its use will counteract asparaginase chemotherapy. Patients often develop hypofibrinogenemia during therapy, but since thrombosis is the typical complication and not bleeding, replacement with cryoprecipitate remains controversial.

Promising new agents for treatment of acute lymphoblastic leukemia

There are many new and promising agents for the treatment of patients with relapsed or refractory ALL. Of the list of agents below, only nelarabine and clofarabine are Food and Drug Administration (FDA) approved agents, and clofarabine is only approved for pediatric patients.

Pathophysiology

ALL represents a vastly heterogeneous set of diseases including both B-cell and T-cell disorders. The pathophysiology of these diseases is undoubtedly reflected in the cytogenetic and molecular abnormalities that are present at diagnosis.

B-cell acute lymphoblastic leukemia

Philadelphia chromosome positive (Ph+) ALL

BCR-ABL1 associated ALL arises from a reciprocal translocation involving chromosomes 9 and 22, t(9;22)(q34;q11.2). The frequency of Ph+ ALL increases with age.

Mixed lineage leukemia

The MLL gene is at 11q23 and chromosomal translocation involving the MLL locus is associated with a large variety of fusion proteins. The most common includes the AF4 gene, t(4;11).

TEL-AML1 (ETV-RUNX1) ALL

The TEL-AML1 translocation, t(12;21)(p13;q22) is the most common chromosomal translocation in the pediatric population, and account for about one quarter of all cases.

Hyperdiploid ALL

B-ALL blasts that contain more than 50 chromosomes are seen in about 25% of pediatric patients and less frequently in older patients. The extra chromosomes are not random, with trisomy of chromosomes 21, X, 14, and 4 being most common. Trisomies of 4, 10, and 17 carry the best overall prognosis.

Hypodiploid ALL

Patients with B-ALL and blasts with less than 45, and particularly those with less than 44 chromosomes have an unusually poor prognosis. This phenotype is seen in about 5% of both children and adults.

E2A-PBX1 (TCF3-PBX1) ALL

The translocation t(1;19)(q23;p13.3) generates a fusion of the E2A (TCF3) gene on chromosome 19 and the PBX1 gene on chromosome 1. The lymphoblasts are usually positive for both CD19 and CD10.

Ikaros and CRLF2 mutations

Both Ikaros and CRLF2 are expressed in about 15% of all cases of B-ALL, regardless of other genetic abnormalities. Expression of these proteins confers an extremely poor prognosis, and the most appropriate treatment strategy for these patients remains undefined.

T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma

T-ALL/LBL can be separated into four distinct subtypes based on immunophenotype patterns that correspond to different stages of intrthymic differentiation; the best prognosis is seen in patients with the thymic (cortical) phenotype:

Pro-T ALL/LBL: positive for cytoplasmic CD3 and CD7, and negative for CD1a, CD2, CD4, and CD8. Pre-T ALL/LBL: positive for cytoplasmic CD3, CD2, and CD7, but negative for CD1a, CD4 and CD8. Cortical (Thymic) T-ALL/LBL: positive for cytoplasmic CD3, CD1a, CD2, and CD7. Also usually positive for both CD4 and CD8. Mature (medullary) T-ALL/LBL: positive for cytoplasmic and surface CD3, CD2, and CD7, but negative for CD1a. Usually only positive for either CD4 or CD8.

Notch mutations: Approximately 50% of cases of adult and pediatric T-ALL/LBL contain activating mutations of the NOTCH1 gene, either within the extracellular heterodimerization domain or within the C-terminal PEST (proline-glutamate-serine-threonine-rich) domain. In addition, 30% of patients have mutations in the FBXW7 gene, which is a negative regulator of NOTCH1.

What other clinical manifestations may help me to diagnose acute lymphoblastic leukemia?

Please refer to the sections on presentation and diagnosis. The clinical presentation of patients with ALL is subtle and include fatigue, lethargy, fevers, night sweats, or weight loss. In addition, patients can present with dyspnea, lightheadedness, infections, or easy bruisability and bleeding. Rarely, children and young adult patients can have a more aggressive or fulminant presentation. Lymphadenopathy, splenomegaly, and hepatomegaly is seen in about 20% of patients with ALL.

In addition to a full review of systems, it is important to focus on symptoms regarding infections such as low-grade fevers or night sweats.

In all patients with ALL, it is important to perform a thorough neurologic examination. For patients with T-cell ALL, one must include radiographic imaging to establish extramedullary sites of disease, such as a mediastinal mass and in male patients, a testicular exam should be a routine part of not only the initial exam, but all follow-up exams as well.

What other additional laboratory studies may be ordered?

N/A

What’s the evidence?

[Dr Gaynon and colleagues from the Children's Cancer Group (CCG) review the treatment regimens and outcomes of pediatric patients over a 2 decade period. During this period, huge improvement in outcomes were realized and changes in the approach of pediatric patients are reviewed.]

[This is an update of a series of well written general reviews that have appeared in the New England Journal of Medicine. Dr. Pui reviews the outcomes of both adult and pediatric patients and reviews new developments in the pathophysiology of ALL. This is a thorough yet concise review of ALL.]

[This is a recent single-institution pediatric study of ALL. The importance of this study is for the reader to review and understand the current approaches to the treatment of pediatric patients with ALL.]

[This CALGB study introduced the 5-drug induction regimen for adults with ALL. This remains one of the more common and important adult ALL regimens. In addition, the use of asparaginase in adult patients was reanalyzed demonstrating improved outcomes and tolerability.]

[The MD Andeson Cancer Center developed a widely popular simplistic approach for the treatment of adults with ALL. This regimen is extremely popular in the US for the treatment of patients with ALL and LBL. This manuscript describes the initial regimen and the reader should be aware that there have been numerous updates and subtle changes to this regimen, especially for patients with T-lineage and Philadelphia chromosome disease.]

[This is a well written review outlining the treatment of patients with Philadelphia chromosome positive ALL, both de novo and in the relapsed setting. In addition, the role of stem cell transplantation is also reviewed.]

[This is a recent retrospective review demonstrating superior outcomes of young adult patients with ALL when they are treated on a pediatric regimen. Sobering for adult oncologists, this study compares and contrasts the different approaches that have been historically used for patients with ALL, and supports the use of pediatric regimens for young adult patients with ALL.]

[Weng and colleagues from the Dana-Farber Cancer Institute demonstrate that approxiamately 60% of both pediatric and adult patients with T-lineage ALL have activating mutations on the NOTCH1 gene. The authors also propose the use of gamma-secretase inhibitors as a potenetial targeted approach for the treatment of patients with relasped or refractory T-lineage ALL.]

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